1. Field of the Invention
This invention relates to a method of inducing antitumor immunocytes, and a process for producing antitumor immunocytes and antitumor immunocytes produced by the process. More particularly, the present invention is concerned with a method of inducing antitumor immunocytes which is simple in operation and suitable for inducing antitumor immunocytes having not only excellent cytotoxic activity against tumor cells but also high safety, which method comprises contacting leucocytes with an insoluble, antitumor immunocyte-inducing material capable of binding to T cells, the antitumor immunocyte-inducing material comprising an insoluble carrier and a ligand linked therewith. The present invention is also concerned with a process for producing antitumor immunocytes and antitumor immunocytes produced by the process.
2. Discussion of Related Art
As is well known, it has been reported that cells such as killer T cells, helper T cells, NK cells, activated macrophages and K cells play an important role as antitumor immunocytes in immunological surveillance with respect to malignant tumors in the living body. Based on the above-mentioned knowledge, there has been proposed, as an immunotherapy for malignant tumors, a method comprising activating immunocytes (leucocytes) of patients with malignant tumors to induce the above-mentioned antitumor immunocytes. However, it is known that the immunological activity of patients with malignant tumors is generally lowered with the progress of the tumors, that immunosuppressive factors which suppress the immuno response exist in the living body of patients with malignant tumors and that suppressor T cells and suppressor macrophages are induced in the living body of patients with malignant tumors [S. Fujimoto et al: J. Immunol., 116, 791 (1976)]. In view of the above, it is recognized to be difficult to efficiently induce antitumor immunocytes in the living body of patients with malignant tumors who are under a suppressed state with respect to immunological activity.
In order to eliminate the drawbacks accompanying the above-mentioned method of inducing antitumor immunocytes in the living body of patients with malignant tumors, many researchers have attempted to induce antitumor immunocytes in vitro by activating leucocytes obtained from patients with malignant tumors. For example, there has been proposed a method of inducing killer T cells in vitro which are considered as playing a leading role in antitumor immunity [Y. Ichino et al: Gann(Cancer), 75, 436 (1984)]. In this method, peripheral blood leucocytes obtained from a patient with a malignant tumor are sensitized with tumor cells obtained from the patient to activate the leucocytes for induction of killer T cells which are cytotoxic for tumor cells of the patient but non-cytotoxic for normal cells of the patient. The thus obtained killer T cells are placed back into the living body of the patient. However, killer T cells induced by the above-mentioned in vitro method do not have a cytotoxic activity sufficient to expect a therapeutical effect.
In order to eliminate the drawbacks of the above-mentioned in vitro method, there have been proposed a method in which killer T cells are incubated using a T cell growth factor which is a kind of lymphokine, thereby increasing the quantity of killer T cells, before administering killer T cells to the patient [Y.Ichino et al: Gann(Cancer), 75, 436 (1984)]. This method is hereinafter often referred to as the "incubation method." The mass production of the T cell growth factor to be used in the incubation method has become possible by virtue of genetic manipulation techniques. Therefore, a large quantity of T cell growth factor can be used for the incubation of killer T cells. In view of the above, it seems that the above-mentioned incubation method could be put to a practical use.
However, the incubation method has the following disadvantages.
(1) Whether or not killer T cells can be induced depends on the patients. That is, this method is not necessarily useful with respect to all the patients with malignant tumors.
(2) Killer T cells should be incubated in vitro for a long period of time (generally one to two months). During the incubation the killer T cells tend to be unfavorably degenerated.
(3) Tumor cells of a patient should be used as an antigen for the sensitization of leucocytes. The tumor cells to be used should be obtained in the living state from tumor tissue of the patient by surgery. This is very troublesome.
(4) The obtained tumor cells should behalf-killed with an antitumor compound so that the tumor cells do not grow. The reason for this is as follows. In the incubation method, the mixture of leucocytes obtained from a patient suffering from a malignant tumor with tumor cells obtained from the patient is incubated to induce killer T cells. The induced killer T cells are then incubated using a T cell growth factor. The obtained killer T cells are then administered to the patient. Needless to say, killer T cells to be administered to the patient should not contain living tumor cells. Therefore, half-killed cells should be used for sensitization of leucocytes.
(5) Even though half-killed tumor cells were used for the sensitization of leucocytes there is a danger of living tumor cells being administered to the patient together with killer T cells. This is a serious problem with respect to the incubation method.
As is apparent from the foregoing, the incubation method is disadvantageous not only from the standpoint of ease in operation but also from the standpoint of safety.